The antitumor properties of a series of structurally simple compounds derived from tropical and subtropical trees of the family Combretaceae are under ongoing investigation. The genus Combretum contains 25 species used in the traditional medical practices of Africa and India. The South African bush willow Combretum caffrum was used by the Zulu and other Southern African people as a charm to ward off enemies and in traditional medical practices.
Combretum caffrum (Eckl. Zehy.) Kuntze collected in 1973 and recollected in 1979 afforded extracts that showed activity in the astrocyte reversal (9ASK) and murine lymphocytic leukemia screening assays of the National Cancer Institute of the U.S.A. Historically, this extract was the first to be successfully fractionated by means of the 9ASK system. In 1982 the isolation of the first member of the combretastatin series was disclosed. Also disclosed was its structure and later synthesis. (Pettit, G. R., et al., Isolation and Structure of Combretastatin, CAn. J. Chem. 1982, 60, 1374-1376; Pettit, G. R., et al., Synthesis of Natural (−)-combretastatin, J. Org. Chem. 1985, 50, 3404-3406.) Subsequently, a number of additional cancer cell line active constituents were isolated. These investigations eventually led to applicant's isolation, structure and synthesis of the cis-stilbene combretastatin A-4 (2a) and its phosphate prodrug (2b). (Pettit, G. R., et al., Isolation and Structure of the Strong Cell Growth and Tubulin Inhibitor Combretastatin A-4, Experentia, 1989, 45, 209-211; Pettit, G. R., et al., Antineoplastic agents 291. Isolation and Synthesis of Combretastatin A-4, A-5, and A-6, J. Med. Chem. 1995, 38, 1666-1672; Ndayikengurukiye, H., et al., Alkoxylated p-phenylenevinylene Oligomers: Synthesis and Spectroscopic and Electrochemical Properties, Tetrahedron 1997, 53, 13811-13828.) The latter has been shown to selectively damage tumor neovasculature with induction of extensive blood flow shutdown in the metastatic tumor compared to normal tissues.
For example, six hours following treatment using the murine CaNT adenocarcinoma and a single i.p. injection of combretastatin A-4 prodrug (100 mg/kg), vascular function shutdown in the tumor was rapid, irreversible and extensive (8). (Ndayikengurukiye, H., et al., Alkoxylated p-phenylenevinylene Oligomers: Synthesis and Spectroscopic and Electrochemical Properties. Tetrahedron 1997, 53, 13811-13828.) In November 1998 four Phase I human cancer trials were initiated, two in the United States and two in England. Current clinical trials (9) have been encouraging and Phase II human cancer clinical trials have been or will be initiated soon. (Cushman, M., et al., Synthesis and Evaluation of Analogues of (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) ethane as Potential Cytotoxic and Antimitotic Agents, J. Med. Chem-1992, 35, 2293-2306.)
The need for such compounds is both critical and ongoing. The isolation of such valuable compounds is the purpose of the present invention.